Patients with a primary tumor (i.e., untreated and located in the organ of origin) often undergo surgery to remove their tumor. Such patients may then receive “adjuvant” therapy with a drug following surgery to target undetectable “micro-metastatic” dormant cancer cells to prevent tumor recurrence and metastasis. In some cases, this therapy may be given prior to surgery (“neoadjuvant” therapy) to also help shrink the primary tumor, but the main purpose is to target micro-metastatic cancer cells.
In patients with recurrent or metastatic cancer, tumors are detectable by routine imaging methods (MRI, PET/CT). A one-centimeter tumor contains around one billion cells and its own micro-environment, complete with blood vessels, regional areas of hypoxia and pH variations, immune cell infiltrate, inflammation, and structural support cells (i.e., fibroblasts, mesenchymal stem cells).
Precision oncology requires delivering the right drug to the right patient at the right time, but “time” is rarely studied in cell culture and animal models before a new drug enters clinical trials. The existing paradigm in clinical drug development is to demonstrate that a new drug is effective against recurrent/metastatic tumors, and then test that drug in the (neo)adjuvant setting to target micro-metastatic cancer cells. This paradigm makes the unfounded assumption that cancer cells within a growing tumor have the same vulnerabilities as dormant cancer cells. As a result, drugs shown to prevent progression of advanced/metastatic solid tumors are sometimes found to be ineffective at preventing cancer recurrence when administered in the (neo)adjuvant setting. The long-term clinical benefit realized from (neo)adjuvant therapies lies in anti-cancer effects on micro-metastatic, dormant cancer cells; the biology underlying such anti-cancer effects is practically unknown, creating a gap for evaluating new drugs.
Understanding how clinically dormant cancer cells vs. established tumors respond to a novel therapy will guide clinical testing in the appropriate disease setting(s), and reveal targets for combination therapies to enhance efficacy. More thorough characterization of drug efficacy in relevant preclinical models will increase the drug success rate in clinical trials, thus decreasing the cost of drug development. Estrogen receptor alpha (ER)-positive breast cancer presents a scenario in which understanding responses of clinically dormant cancer cells vs. established tumors to treatment with novel therapies would have a significant global impact. ER+ breast cancer causes more recurrences and deaths than all other breast cancer subtypes combined. Patients with early-stage (non-metastatic) ER+ breast cancer are treated with adjuvant anti-estrogen therapies that block ER activity and reduce breast cancer recurrence. However, approximately 1/3 of these patients (~300,000 women per year worldwide) ultimately experience local and/or distant recurrence. Despite adjuvant anti-estrogen therapies, micro-metastatic dormant cancer cells persist, suggesting that such cells are growth-suppressed but not eliminated by anti-estrogens; eliminating such clinically dormant cancer cells would prevent recurrence.